For an individual, chronic tobacco use is associated with a significant increase in heart disease and many forms of cancer;the health of non-tobacco users is negatively affected by second- hand smoke. The potential benefits that would come from a better understanding of the etiology of nicotine dependence are enormous. Approaches to addiction that include Pavlovian conditioning processes have lead to important advances in our understanding and treatment of drug use in general, and nicotine dependence specifically. These approaches most often treat nicotine as an unconditioned stimulus that enters into an association with other stimuli (cigarette, situational cues) that reliably co-occur with its effects. Albeit less studied, also of import to the development and tenacity of nicotine dependence is the ability of the pharmacological effects of nicotine to serve as an interoceptive stimulus for other reinforcing events (peer acceptance, alcohol, work breaks, stress relief, etc.). In a preclinical model, rats that have such an appetitive learning history with nicotine will show evidence of conditioning controlled by the nicotine stimulus. This conditioning follows many of the known principles of conditioning and does not reflect state-dependent learning. The most provocative finding to date is that conditioning to the nicotine stimulus can be weakened by repeated non-reinforced presentation of an alternative drug (i.e., extinction) that shares interoceptive stimulus properties with nicotine. This "transfer of extinction" has been seen with varenicline (the smoking cessation aid Chantix(R)) and nornicotine (a potential smoking cessation aid that is a metabolite of nicotine). This competing renewal will build programmatically on the progress from the previous funding period by examining more closely extinction with nicotine and the transfer of extinction in a series of carefully designed experiments. These experiments will provide insight into the nature of the nicotine stimulus and related drugs such as varenicline, as well as identify basic processes underlying extinction learning with nicotine. RELEVANCE: A better understanding of excitatory associations involving the interoceptive stimulus effect nicotine and how the expression of such associations are affected by non-reinforcement, including non- reinforcement with pharmacologically related drugs will provide new an important insights into factors contributing to chronic tobacco use and the tenacity of nicotine dependence. Such insights can be used to design better behavioral and pharmacological treatments. PUBLIC HEALTH RELEVANCE: Tobacco use reflects a major health problem that results from an addiction to nicotine. With an estimated annual economic cost around $167 billion, this nicotine addiction is associated with a significant increase in heart disease and many forms of cancer;the health of non-tobacco users is also negatively affected by second-hand smoke. The potential benefits that would come from a better understanding of chronic tobacco use are enormous and this benefit is the primary reason the long-term goal of our research program is to elucidate potential associative learning processes contributing to nicotine dependence.